sORFs

Small open reading frames (sORFs) are short stretches of nucleotides that can be translated into small peptides, typically encoding fewer than 100 amino acids. They are found throughout genomes, including in annotated protein-coding genes, untranslated regions (5' UTRs and 3' UTRs), long noncoding RNAs, and intergenic regions. sORFs are widespread in bacteria, archaea, and eukaryotes, and in organellar genomes.

This class was historically neglected due to small size and biases against short coding sequences in gene prediction. Advances in ribosome profiling (Ribo-seq) and targeted proteomics have revealed many translated sORFs. Computational pipelines assess features such as start/stop codons, length, codon usage, conservation, and ribosome occupancy, but coding potential can be ambiguous.

Contexts: uORFs in 5' UTRs can regulate downstream translation; overlapping sORFs may coincide with annotated CDSs; downstream ORFs and intragenic sORFs contribute to regulatory networks. In coding regions, sORFs can encode micropeptides that influence membrane function, signaling, or metabolism; in noncoding RNAs, sORFs can add coding capacity or act via peptide-independent mechanisms.

Functionality: Some sORFs have validated roles in development, stress responses, and cellular signaling; others remain uncharacterized. Conservation across species is used as evidence for function, but many sORFs show lineage-specific retention.

Annotation and resources: Specialized databases such as sORFs.org, OpenProt, and the sORF database curate predicted and validated sORFs. Experimental validation remains essential.